Mechanistic studies explain why single-agent BRAF inhibitors—highly effective in melanoma—produce only limited activity in CRC: feedback reactivation of upstream EGFR signaling and rapid MAPK pathway re-engagement (via RAS activation or alternative RAF dimerization) circumvent RAF blockade, resulting in primary resistance in many BRAF-mutant CRC. This evidence concerns the gene BRAF and colorectal carcinoma.